This proposal addresses the behavioral consequences of monoaminergic regulation of MeCP2, a methyl- DNA binding protein that plays a role in synapse development and whose loss-of-function mutations result in the neurodevelopmental disorder Rett syndrome. Our preliminary data show that MeCP2 is rapidly phosphorylated in response to psychostimulant exposure at Ser421, and that mice bearing a point mutation at Ser421 exhibit altered behavioral sensitization and conditioned place preference, implicating a role for pMeCP2 in behavioral plasticity. Here we hypothesize that activation of monoaminergic signaling regulates MeCP2 phosphorylation at Ser421, and this phosphorylation event contributes to some of the synaptic and behavioral adaptations that result from chronic activations of monoaminergic signaling. We plan to further characterize the role pMeCP2 plays in reward-directed behavior; the results of these experiments may suggest other monoaminergic-behaviors in which the phosphorylation event is involved. We will also investigate the molecular mechanisms that underlie the altered behavioral adaptations to chronic AMPH in the Ser421 mutant mice by examining synapse structure and function. The results from these experiments could support a role for MeCP2 phosphorylation in transducing chronic monoaminergic signaling into persistent changes in behavior. PUBLIC HEALTH RELEVANCE: Drug addiction is a persistent, debilitating psychiatric disease characterized by uncontrollable drug-taking; even after long periods of abstinence, the risk of relapse is very high. Here we propose to investigate monoaminergic regulation of MeCP2, a methyl-DNA binding protein that via changes in synapse structure or function may contribute to persistent behavioral adaptation. Understanding the molecular mechanisms downstream of psychostimulants may uncover novel targets for therapy.